Novel Protective Role for Ubiquitin-Specific Protease 18 in Pathological Cardiac Remodeling.
Novel Protective Role for Ubiquitin-Specific Protease 18 in Pathological Cardiac Remodeling.
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泛素特异性蛋白酶 18 在病理性心脏重塑中的新保护作用。
DOI：
10.1161/hypertensionaha.116.07562
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发表时间：
2016
期刊：
影响因子：
8.3
通讯作者：
He Ben
中科院分区：
文献类型：
--
作者：
Ying Xiaoying;Zhao Yichao;Yao Tianbao;Yuan Ancai;Xu Longwei;Gao Lingchen;Ding Song;Ding Hongyi;Pu Jun;He Ben
泛素特异性蛋白水解酶18(USP18)是USP家族成员之一，参与抗病毒活性和肿瘤抑制作用。虽然USP18在心脏中表达，但USP18在心脏和心脏疾病中的作用尚不清楚。在这里，我们发现USP18在人类扩张的心脏和肥大的小鼠模型中的表达都升高。在小鼠中，心肌细胞特异性的USP18过表达显著钝化心脏重塑，表现为减轻心肌肥大、纤维化、心室扩张和保留射血功能，而USP18缺陷小鼠在相同的病理刺激下表现出加剧的心脏重塑。血管紧张素II诱导的新生大鼠心肌细胞肥大也有类似的结果。USP18在肥大刺激下的抗肥大作用与阻断转化生长因子活化的蛋白激酶1-p38/c-jun氨基末端蛋白激酶1/2信号转导通路有关。用一种药物抑制剂(5Z-7-oxozeaenol)阻断转化生长因子活化的激酶1-p38/c-jun氨基末端激酶1/2信号转导，可极大地逆转USP18基因敲除小鼠主动脉结扎术中观察到的不利影响。我们的数据表明，USP18在重塑过程中抑制心肌肥厚和延缓心功能不全，这依赖于它对转化生长因子激活的激酶1-p38/c-jun氨基末端激酶1/2信号轴的调节。因此，USP18是治疗心力衰竭的有效靶点。
Ubiquitin-specific protease 18 (USP18), a USP family member, is involved in antiviral activity and cancer inhibition. Although USP18 is expressed in heart, the role of USP18 in the heart and in cardiac diseases remains unknown. Here, we show that USP18 expression is elevated in both human dilated hearts and hypertrophic murine models. Cardiomyocyte-specific overexpression of USP18 in mice significantly blunted cardiac remodeling as evidenced by mitigated myocardial hypertrophy, fibrosis, ventricular dilation, and preserved ejection function, whereas USP18-deficient mice displayed exacerbated cardiac remodeling under the same pathological stimuli. Similar results were observed for in vitro angiotensin II–induced neonatal rat cardiomyocyte hypertrophy. The antihypertrophic effects of USP18 under hypertrophic stimuli were associated with the blockage of the transforming growth factor-&bgr;–activated kinase 1-p38/c-Jun N-terminal kinase 1/2 signaling cascade. Blocking transforming growth factor-&bgr;–activated kinase 1-p38/c-Jun N-terminal kinase 1/2 signaling with a pharmacological inhibitor (5Z-7-oxozeaenol) greatly reversed the detrimental effects observed in USP18-knockout mice subjected to aortic banding. Our data indicate that USP18 inhibits cardiac hypertrophy and postpones cardiac dysfunction during the remodeling process, which is dependent on its modulation of the transforming growth factor-&bgr;–activated kinase 1-p38/c-Jun N-terminal kinase 1/2 signaling axis. Thus, USP18 is a potent therapeutic target for heart failure treatment.